Feto-maternal Ratio Research Articles

Factors associated with partitioning behavior of persistent organic pollutants in a feto-maternal system: A multiple linear regression approach

Prenatal exposure to persistent organic pollutants (POPs) has been a matter of particular concern because such exposure can severely affect the health of the fetus. The mechanistic understanding of the partitioning behavior of POPs in the feto-maternal system and the associated factors, however, have rarely been studied. Here, we employed a new approach based on multiple linear regression (MLR) analysis to predict the feto-maternal ratio (FM-ratio) of POPs and to assess the factors associated with feto-maternal partitioning behavior. Two preliminary exploratory MLR models were built using physiological conditions of the participants, and molecular descriptors were calculated with a computational model. The FM-ratio was calculated from the concentrations of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polybrominated diphenyl ethers (PBDEs) in 20 pairs of maternal and cord blood. The models showed that the lipids and cholesterols in the maternal and cord blood and the placenta significantly influence the partitioning of POPs. The body mass index (BMI) change during pregnancy was also related to the FM-ratio. The physicochemical properties associated with lipophilicity and molecular size were also related to the FM-ratio. Even though the results should be interpreted with caution, the preliminary MLR models illustrate that feto-maternal partitioning is governed by transplacental transporting mechanisms, toxicokinetics, and the molecular physicochemical properties of POPs. Overall, the new approach used in this study can improve our understanding of the partitioning behavior in the feto-maternal system.

Serum Zinc, Copper and Albumin in Paired Mothers and Their Term Newborn in a Tertiary Hospital in Nigeria

Objective: This study assessed the serum zinc, copper and albumin levels in paired mother and newborns in the immediate neonatal period to establish the relationship between the pair, and the influence of maternal micronutrient status on that of the newborn if any. Methods: The sociodemographic characteristics of the mothers were obtained using a structured questioner after informed consent was obtained from the parents of the baby. At delivery, paired mother and newborns had their serum zinc, copper and albumin assayed, using cord blood in the newborn. Result: One hundred and thirty five mothers and their paired term newborns completed the study. The mean age of the mothers was 29.2 ± 4.6 years with 67% within the age bracket 20 to 30 years. Seventy three percent of the mothers attained tertiary education and 22% had secondary education. The mean serum zinc was significantly higher in the newborn (3.67 ± 1.49 μmol/L) than in the mothers (2.20 ± 1.01 μmol/L), p = 0.0001, with a feto-maternal ratio of 1.6 to 1. Copper was significantly higher in the mothers (4.27 ± 1.77 μmol/L), than in the newborns (2.84 ± 0.92 μmol/L) (p = 0.001), with a maternal-fetal ratio of 1.5 to 1. Mean serum albumin was significantly lower in the newborns than in the mothers (p > 0.011). Conclusion: This study established that term newborns have higher serum zinc, a lower serum copper and albumin levels than their maternal levels. The distribution of these trace elements is probably protective in the newborns against infection.

Maternal depression attenuates newborn vitamin D concentrations in winter-spring: a prospective population-based study

We aimed to investigate whether the newborns of mothers with maternal depression (MD) had lower vitamin D levels than newborns of non-MD (NMD) mothers and identify the potential mechanism underlying this association. Maternal depressive symptoms in late pregnancy and concentrations of cord blood 25 hydroxyvitamin D (25(OH)D) were measured in 1491 mother-infant pairs. Data on maternal sociodemographic characteristics, health status, lifestyle and birth outcomes were prospectively collected. For infants born in winter-spring, the infants of MD mothers had significantly reduced concentrations of 25(OH) D (adjusted β = −3.51 nmol/L; 95% CI: −6.19, −0.84; P = 0.010) and lower birth weight (3267 ± 470 g vs 3348 ± 598 g, F = 4.64, P = 0.031), compared with the infants of NMD mothers. A significant, inverse linear relationship was noted between maternal depression scores and the concentration of 25(OH)D for infants born in winter-spring (adjusted β = −0.158; 95% CI: −0.259, −0.057). The significant, inverse linear relationship between maternal depression scores and fetomaternal ratios of 25(OH) D was also observed among the infants born in winter-spring (adjusted β = −0.005; 95% CI: −0.008, −0.003). MD appears to significantly attenuate the vitamin D concentrations and birth weight of infants born in winter-spring. A decreased fetomaternal ratio of 25(OH)D might be involved in this biological pathway.

474: Placenta transfer of sildenafil citrate in the ex-vivo human cotyledon perfusion model

Sildenafil is currently being administered to pregnant patients with pulmonary hypertension and is under evaluation as a treatment for several placental complications, such as pre-eclampsia and intrauterine growth restriction. Since animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature and airway complexity. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required. Herein we aimed to measure transplacental transfer of sildenafil using the ex-vivo human placental perfusion model. Six placentas were collected after term delivery from healthy volunteers, cannulated and dually perfused. Sildenafil citrate was added to the maternal circulation at two different concentrations: 500 ng/mL (N=3) and 50 ng/mL (N=3), representing the maximal tolerated concentration (MC) and the therapeutic concentration (TC), respectively. Anti-pyrine (AP) 100ug/mL was also added to the maternal reservoir and used as internal control. Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150 and 180 min, and the concentration of sildenafil and its metabolite desmethyl (DM)-sildenafil was determined using high performance liquid chromatography. Feto-maternal (FM) ratio (fetal/maternal concentration) and normalized FM ratio (sildenafil FM ratio/AP FM ratio) were calculated for each time-point. Transfer clearance was calculated as the rate of fetal excretion/maternal concentration. Sildenafil crossed the placenta at both concentrations. Both maternal and fetal levels reached a plateau at 90-120 min. Median transfer clearance during the first two hours was 1.20 (IQR 0.50) mL/min for MC and 1.43 (IQR 0.31) mL/min for TC. At steady state (180 min), the median FM ratio was 0.94 (IQR 0.21) and 1.15 (IQR 0.11), and the median normalized FM ratio was 1 (IQR 0.21) and 1.24 (IQR 0.05) for MC and TC respectively (Figure 1). DM-sildenafil was not detected in any sample. Sildenafil crosses the term placenta at a relatively high rate ex-vivo, suggesting that there is sufficient placental transfer to reach therapeutic fetal drug levels at non-toxic maternal dose.

Criteria and challenges of the human placental perfusion – Data from a large series of perfusions

Perfusion of human placental cotyledon has been used extensively to study transplacental transfer of endogenous and exogenous compounds. However, many challenges in the use of the method exist, including availability of placentas and complexity of the method itself. In Kuopio, Finland we have carried out human placental perfusions since 2005 using the same method with data now from over one hundred perfusions. This has allowed us to study whether the way of delivery, placental weight, and/or the length of pregnancy affect the two major criteria of a successful perfusion: volume loss (leak) from fetal to maternal circulation, and transplacental transfer of the reference compound antipyrine. The only statistically significant result was the reduction of the fetomaternal ratio of antipyrine by the placental age over 40weeks (p=0.0004). The success criteria were not affected by the weight of the placenta or the way of delivery. There was no effect by the antipyrine concentration on antipyrine transfer. In vitro incubation with different concentrations of study compounds and different tubing materials could offer an easy way to study potentially reduced recovery due to binding to perfusion system.

Transplacental Supply of Mannose and Inositol in Uncomplicated Pregnancies Using Stable Isotopes

The aim of this study was to determine relative contributions of transplacental flux vs. fetal production for inositol and mannose in normal term pregnancies. Seven term uncomplicated pregnancies undergoing cesarean section were infused with (13)C- and (2)H-labeled isotopes of glucose, inositol, and mannose until a steady state was achieved. Maternal and fetal concentrations of labeled and unlabeled glucose, mannose, and inositol were measured using gas chromatography/mass spectroscopy. The fetomaternal molar percentage excess ratio was calculated for each glucose, mannose, and inositol. The fetomaternal molar percentage excess ratio of mannose in the fetal artery (F(artery)/M) was 0.99 [97.5% confidence interval (CI), 0.91-1.07] and in the fetal vein (F(vein)/M), 1.02 (97.5% CI, 0.95-1.10). Both were not significantly different from 1.0, consistent with transplacental supply. The fetomaternal ratios for glucose were similar to mannose (fetal artery, 0.95; 97.5% CI, 0.84-1.15; and fetal vein, 0.96; 97.5% CI, 0.85-1.07). The fetomaternal ratio for inositol was significantly less than 1.0 (fetal artery, 0.08; 97.5% CI, 0.05-0.12; fetal vein, 0.12; 97.5% CI, 0.06-0.18), indicating little transplacental flux and significant fetal production. In normal term pregnancies, fetal mannose and glucose concentrations are dependent upon maternal transplacental supply. Fetal inositol is not dependent upon transplacental supply.

Transfer of PAMAM dendrimers across human placenta: Prospects of its use as drug carrier during pregnancy

Dendrimers offer significant potential as nanocarriers for targeted delivery of drugs and imaging agents. The objectives of this study were to evaluate the transplacental transport, kinetics and biodistribution of PAMAM dendrimers ex-vivo across the human placenta in comparison with antipyrine, a freely diffusible molecule, using dually perfused re-circulating term human placental lobules. The purpose of this study is to determine if dendrimers as drug carriers can be used to design drug delivery systems directed at selectively treating either the mother or the fetus. The transplacental transfers of fluorescently (Alexa 488) tagged PAMAM dendrimer (16 kDa) and antipyrine (188 Da) from maternal to fetal circulation were measured using HPLC/dual UV and fluorescent detector (sensitivity of 10 ng/mL for dendrimer and 100 ng/mL for antipyrine respectively). C max for the dendrimer–Alexa (DA) in maternal perfusate (T max = 15 min) was 18 times higher than in the fetal perfusate and never equilibrated with the maternal perfusate during 5.5 h of perfusion (n = 4). DA exhibited a measurable but low transplacental transport of 2.26 ± 0.12 μg/mL during 5.5 h, where the mean transplacental transfer was 0.84 ± 0.11% of the total maternal concentration and the feto-maternal ratio as percent was 0.073% ± 0.02. The biochemical and physiological analysis of the placentae perfused with DA demonstrated normal function throughout the perfusion. The immunofluorescence histochemistry confirmed that the biodistribution of DA in perfused placenta was sparsely dispersed, and when noted was principally seen in the inter-villous spaces and outer rim of the villous branches. In a few cases, DA was found internalized and localized in nuclei and cytoplasm of syncytiotrophoblast and inside the villous core; however, DA was mostly absent from the villous capillaries. In conclusion, the PAMAM dendrimers exhibited a low rate of transfer from maternal to the fetal side across the perfused human placenta, which is similar to other investigations of large macromolecules, e.g., IgG. These overall findings suggest that entry of drugs conjugated to polymers, i.e., dendrimers, would be limited in their transfer across the human placenta when compared to smaller drug molecules alone, suggesting novel methods for selectively delivering therapeutics to the pregnant woman without significant transfer to the fetus, especially since the half life of the dendrimer in blood is relatively short.

Transplacental Transfer of Monomethyl Phthalate and Mono(2-ethylhexyl) Phthalate in a Human Placenta Perfusion System

The transplacental passage of monomethylphtalate (mMP) and mono (2-ethylhexyl) phthalate (mEHP) was studied using an ex vivo placental perfusion model with simultaneous perfusion of fetal and maternal circulation in a single cotyledon. Umbilical cord blood and placental tissue collected both before and after perfusion were also analyzed. Placentas were obtained immediately after elective cesarean section and dually perfused in a recirculation system. mMP or mEHP was added to maternal perfusion medium to obtain concentrations at 10 and 25 microg/L, respectively. The placental transfer was followed analyzing samples from fetal and maternal perfusion media by liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS). Four perfusions with mMP indicated a slow transplacental transfer, with a feto-maternal ratio (FM ratio) of 0.30 +/- 0.03 after 150 min of perfusion. Four perfusions with mEHP indicated a very slow or nonexisting placental transfer. mEHP was only detected in fetal perfusion media from two perfusions, giving rise to FM ratios of 0.088 and 0.20 after 150 min of perfusion. Detectable levels of mMP, mEHP, monoethylphthalate (mEP), and monobutylphthalate were found in tissue. Higher tissue levels of mMP after perfusions with mMP compared to perfusions with mEHP suggest an accumulation of mMP during perfusion. No tendency for accumulation of mEHP was observed during perfusions with mEHP compared to perfusions with mMP. Detectable levels of mEHP and mEP were found in umbilical cord plasma samples. mMP and possibly other short-chained phthalate monoesters in maternal blood can cross the placenta by slow transfer, whereas the results indicate no placental transfer of mEHP. Further studies are recommended.

Relation of ANP and BNP to their N-terminal fragments in fetal circulation: evidence for enhanced neutral endopeptidase activity and resistance of BNP to neutral endopeptidase in the fetus.

To investigate the role of neutral endopeptidase in the turnover of atrial (ANP) and brain (BNP) natriuretic peptides and their N-terminal fragments in human fetal circulation. Retrospective case-control study. Department of Obstetrics and Gynaecology, University of Leipzig, Germany. Nine control pregnancies and nine pregnancies with rhesus isoimmunisation before and after intravascular transfusion. Natriuretic peptides and N-terminal fragments in maternal and fetal blood were measured by radio-immunoassay. Neutral endopeptidase activity was determined by HPLC. Maternal and fetal plasma concentrations of ANP, NT-proANP, BNP, NT-proBNP as well as neutral endopeptidase activity. Ratios between mature peptide and N-terminal fragment. Feto-maternal ratio. Plasma NT-proANP concentrations are 11.7 times higher in fetal than in maternal circulation. The ANP concentration is only 1.8 times higher, probably due to doubled neutral endopeptidase activity. In contrast, both NT-proBNP and BNP are doubled in fetal plasma. Fetuses with Rh isoimmunisation had significantly higher NT-proBNP but not NT-proANP and neutral endopeptidase activity than controls. An additional volume load by intravascular transfusion did not influence N-terminal fragments or neutral endopeptidase activity. Our study is the first to determine NT-pro natriuretic peptide concentrations and neutral endopeptidase activity in human fetuses. The results show that increased fetal neutral endopeptidase activity shifts the ANP/NT-proANP but not the BNP/NT-proBNP ratio and that the shifted BNP/NT-proBNP ratio in fetuses with Rh isoimmunisation does not involve increased neutral endopeptidase activity. These findings point to a BNP degradation that is not dependent on neutral endopeptidase.

An examination of whether human placental perfusion allows accurate prediction of placental drug transport: Studies with diazepam

Introduction: Presently, no well-validated predictive tools are available for human placental transfer. We studied the transplacental passage of diazepam (DZP) in a recirculating dual human placental perfusion and compared the data with in vivo clinical data from the literature. Methods: Term placentas from healthy mothers without medication were used. The dual, recirculating perfusion technique was used. DZP (2 μg/ml, n=4; 200 ng/ml, n=3) and the reference compound antipyrine (100 μg/ml) were added into the maternal circulation simultaneously. The disappearance of drugs from the maternal circulation and appearance into the fetal circulation were followed every 15 min for 2 h. Results: DZP was detectable in the fetal circulation within 15 min in all of the perfusions indicating rapid transfer. DZP concentrations in the maternal circulation were higher than in the fetal circulation throughout the perfusion with both initial concentrations. At the end of the perfusion, the feto-maternal ratio was 0.48±0.11 (mean±S.D.) and the transfer from the maternal to the fetal compartment 18.4±3.6% with 2 μg/ml of DZP and 0.55±0.10 and 20.5±3.1% with 200 ng/ml of DZP, respectively. DZP concentrations in the perfused area of the placenta were in average 2 times higher than in the maternal perfusate and 3.6 times higher than in the fetal perfusate. Total recovery of DZP from samples, perfusion fluid, and perfused tissue was 37.6±21%. Discussion: Since animal studies in vivo do not accurately predict human placental transfer and it is problematic to study placental transfer of drugs in humans in vivo, the present human placental perfusion system could serve as one part of a test battery for fetotoxicity. However, although our earlier studies and those from the literature indicate a good correlation between in vivo and placental perfusion data, the present study shows this is not the case for all drugs.

Placental transfer of cotinine at 12–17 weeks of gestation and at term in heavy smokers

The objective of this study was to compare the placental transfer of cotinine from maternal to fetal circulation in heavy chronic smokers during the second trimester of pregnancy and at term. Maternal and fetal cotinine concentrations were evaluated in 26 women requesting surgical termination for psychosocial reasons at 12–17 weeks gestation and 26 women with uncomplicated pregnancies at 37–40 weeks gestation, and delivered vaginally. Cotinine concentrations were measured by radioimmunoassay. At 12–17 weeks, the median cotinine concentration was significantly ( P = 0.009) lower in fetal than in maternal serum. At term fetal and maternal cotinine concentrations were similar. The feto–maternal ratio was significantly ( P < 0.001) lower in second trimester pregnancies than in term pregnancies. In both groups, positive linear correlations were found between maternal and fetal serum cotinine concentration and between maternal serum cotinine concentration and the number of cigarettes smoked per day. These data indicate that placental cotinine transfer increases with advancing gestation. This may be secondary to increased placental permeability in the third trimester, which could be linked to progressive placental damage in heavy chronic smokers.

Chronic maternal smoking and cord blood amino acid and enzyme levels at term

Objective: To assess the influence of chronic active maternal smoking on cord blood amino acid and enzyme levels at term. Methods: The concentrations of 24 free amino acids, total protein, and five enzymes were measured in samples of maternal and fetal cord venous plasma from 24 nonsmokers who were not exposed to tobacco smoke and 24 chronic smokers. Cotinine levels were also measured in maternal plasma to evaluate fetal tobacco exposure. The pregnancies were between 37 and 40 weeks’ gestation, were uncomplicated, and were delivered vaginally. Results: Fetal weight was significantly ( P < .01) lower in the smokers than in controls. A positive significant ( P < .001) correlation was found between maternal and umbilical venous cotinine concentrations. Significantly lower concentrations of aspartic acid ( P < .01), hydroxyproline ( P < .05), threonine ( P < .005), alanine ( P < .05), α-aminobutyric acid ( P < .001), methionine ( P < .05), tyrosine ( P < .001), phenylalanine ( P < .01), and lysine ( P < .05) were found in the venous cord plasma of the smokers compared with nonsmokers. The fetomaternal ratios were similar in both groups. The umbilical plasma alkaline phosphatase activity was significantly ( P < .01) lower in the smokers than in the controls. Conclusion: Chronic maternal smoking is associated with alterations of protein metabolism and enzyme activity in fetal cord blood. These may be secondary to irreversible changes in the cellular functions of the trophoblast and may contribute to fetal growth restriction.

Placental transport of maternal immunoglobulin G in pregnancies at risk of Rh (D) hemolytic disease of the newborn.

The following questions were addressed: Is the placental transport of immunoglobulin (Ig)G, IgG1, and IgG3 diminished in pregnancies at risk of hemolytic disease of the newborn? Is the placental transport of IgG, IgG1, and IgG3 correlated with the hemoglobin concentration in the fetus and AutoAnalyzer (AA) quantitations of maternal anti-D? IgG concentrations were determined retrospectively in 41 paired fetal/maternal (f/m) samples in 31 Rh (D) alloimmunized pregnancies. IgG1 and IgG3 concentrations were determined in those 23 cases in which the results of fetal hemoglobin concentration and quantitations of maternal anti-D were available. The results were compared with values found in normal pregnancy and correlated with maternal anti-D AA quantitations and fetal hemoglobin concentrations. Fetal IgG, IgG1, and IgG3 concentrations, and the corresponding fetomaternal ratios in Rh (D) alloimmunized pregnancies, increased with gestational age according to the following formulas (obtained by simple regression): Fetal IgG = -8.846 + 0.491.gestational age (GA), (R2 = 0.544); fetal IgG = 10.021 + 0.46.GA (R2 = 0.463); fetal IgG3 = -0.865 + 0.039.GA, (R2 = 0.327); f/m IgG = -1.006 + 0.054.GA, (R2 = 0.557); f/m IgG1 = -1.876 + 0.085.GA, (R2 = 0.654); f/m IgG3 = -0.199 + 0.026.GA, (R2 = 0.146). The placental transport of IgG, IgG1, and IgG3 in women with Rh (D) immunizations is not diminished compared with normal pregnancy. However, AA quantitations of anti-D are inversely correlated with f/m IgG ratio, f/m IgG1 ratio, and fetal IgG and IgG1 concentrations (P = 0.002, P = 0.004, P = 0.02, and P = 0.02 respectively). The placental transport of IgG3 is significantly higher in pregnancies at risk of hemolytic disease of the newborn compared with IgG3 concentrations in normal pregnancy.

Placental transport of maternal immunoglobulin G.

How does the placental transport of immunoglobulin G (IgG) vary with gestational age? MEDLINE was searched for the appearance of "pregnancy" and "IgG" in the title or abstract from 1966 up to 1995. All publications were reviewed for any kind of IgG data from the fetus and the mother and "known" gestational age. In total, 96 publications from the MEDLINE search fulfilled the search criteria. Seven of ninety-six publications contained IgG and gestational age data from the fetus and/or the mother. Five other publications that fulfilled the same criteria were also available and were also included. Fetal serum IgG concentrations were found to increase with gestational age according to the formula: fetal IgG = 13.564 - 1.094 x gestational age (GA) + 0.026 x GA2 (R2 = 0.877). The fetomaternal (f/m) ratio was also found to increase with gestational age according to the formula: f/m IgG = 0.399 - 0.059 x GA + 0.003 x GA2 - 2.065 x 10(-5) x GA3 (R2 = 0.831). The fetal IgG concentrations exceed maternal IgG concentrations after the 35th week of pregnancy. The fetal IgG concentrations are extremely low in the beginning of pregnancy, they exceed 2.5 g/L at > 25 pregnancy weeks, and they reach 5 g/L at pregnancy week 30.

Transport and metabolism of thyrotrophin-releasing hormone across the fetal membrane.

To determine the transfer and metabolism of TRH by human fetal membranes, the bidirectional transport and uptake of TRH was investigated by adding 125I-labeled TRH (100,000 cpm) or commercial TRH either to the maternal or the fetal compartment of an in vitro model of cultured human fetal membranes obtained from term and preterm placenta. Transmembrane transfer was also studied in the presence of 200 microM p-hydroxy-mercuriphenyl-sulphonic acid (p-HMSA), a dipeptidase enzyme inhibitor. Creatinine and heparin were used as an internal markers. Metabolites of TRH were separated from intact molecules by gel filtration on Sephadex G-10. The structural integrity of the membrane was confirmed by electron microscopy. The transmembrane transfer of radiolabeled and commercial TRH were comparable across both preterm and term placenta. When transport was studied from the maternal to fetal side, the maternal concentration of TRH declined rapidly from 100% at time 0 to 19.31 +/- 2.26% at 8 h with a concomitant increase in the fetal concentration from undetectable to a maximum of 2.56 +/- 0.38% with a fetomaternal ratio of 0.16 +/- 0.01. Transfer of TRH from the fetal to maternal compartment was similar to that of maternal to fetal. Chromatography of maternal and fetal media showed that TRH was metabolized by the membrane into small molecular weight fragments. Treatment of the membrane with p-HMSA increased TRH transport from the maternal to fetal compartment to 18.12 +/- 0.91 (P < 0.001) with an fetomaternal ratio of 0.35 +/- 0.02 (P < 0.001). Although transmembrane transfer of TRH from the fetal to maternal side was also increased by p-HMSA, levels achieved were less than that from maternal to fetal (12.26 +/- 1.50%; P < 0.05). These results suggest that the human fetal membrane acts as an enzymatic barrier to the bidirectional transfer of TRH from 24 weeks gestation.

Pharmacokinetic Examination of p-Aminobenzoic Acid Passage through the Placenta and the Small Intestine in Rats

In the present study the permeability of the rat small intestine and the placenta to p-aminobenzoic acid (PABA) and antipyrine (AP) was investigated. Perfusion of the rat term placenta was used to determine the materno-fetal transfer of both compounds. PABA appeared in the fetal compartment faster than AP (ktransfer = 0.064 and 0.046 min-1, respectively). The rate of equilibration between the maternal and fetal compartments and placental clearance were lower for PABA than for AP (keqilibration = 0.011 and 0.020 min-1; Clp = 0.22 and 0.33 ml/min, respectively); the feto-maternal concentration ratios at equilibrium (FMCReq) were, however, mutually comparable. Similarly, PABA proved to be absorbed from the small intestine significantly faster than AP (ka = 0.824 min-1 and 0.479 min-1; tmax = 3.1 min and 8.9 min, respectively.The apparent volume of distribution (Vd) of AP in non-pregnant animals showed that the drug is distributed into the whole body water as expected (Vd = 0.66 1/kg); however, Vd of AP in pregnant animals was estimated to be 1.81 1/kg. Vd of PABA in non-pregnant animals showed its partially limited distribution, which was only slightly increased in the pregnant animals.Our results confirmed a faster penetration of hydrophilic PABA across the placenta and the small intestine than that of lipophilic AP. The mechanism of transplacental passage of PABA, however, remains to be determined.

Transfer and metabolism of thyrotropin releasing hormone across the perfused human term placenta.

The transport and uptake of TRH was investigated in the maternal-fetal-placental unit of perfused human term placenta. The degradation of TRH in biological fluid was first determined by incubating [125I]TRH with 100 microL 50% maternal or cord sera with or without pretreatment with 200 microM of p-hydroxymercuriphenyl sulfonic acid (p-HMSA), a proline dipeptidase inhibitor. Transplacental transfer of TRH was then studied by adding 10 microCi of [125I]- or [3H]TRH to the maternal circulation of dually perfused isolated lobule of human term placenta with or without 200 microM p-HMSA. Creatinine was used as an internal marker. The rate of degradation of TRH (P < 0.001) and inhibition by p-HMSA were significantly higher in maternal than cord sera (P < 0.05). In the maternal circulation, TRH concentration declined rapidly from 100% at time 0 to 33.5 +/- 1.2% at 120 min. The fetal concentration increased from undetectable levels to a maximum of 1.8 +/- 0.3% at 120 min with a low feto-maternal ratio (0.08 +/- 0.02). Perfusion in the presence of p-HMSA, however, did not significantly change fetal concentration, or the maternal and fetal concentration-time integral levels of TRH. Chromatography of maternal, fetal, and placental homogenates showed that TRH was metabolized by the placenta into small molecular weight fragments predominantly released in the maternal circulation. These results suggest that human placenta acts as an enzymatic barrier to the free passage of TRH.

Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate.

Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30-150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng.ml-1 in mother plasma samples and from 3.0 to 46.6 ng.ml-1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.

Placental transfer of theophylline in an in vitro closed perfusion system of human placenta isolated lobule.

Theophylline (TH) is a methylated xanthine widely used in the treatment of asthmatic pregnant women. Because of the scant available information on the transplacental profile, the time course of TH transfer was studied by an in vitro human placental perfusion. 6 placentas were perfused with Earle's enriched bicarbonate buffer for 180 min using recirculating maternal and fetal circuits. The physiological and biochemical properties of the tissue were well maintained. TH data were compared to those of antipyrine (AP), an usual marker in placental perfusions. The disappearance of TH from the maternal circuit was studied after administration of 15 mg/l in maternal perfusate. TH appeared in the fetal circuit within 5 min. Equilibrium was achieved in both circuits. TH fetomaternal mass ratio became constant (FMM = 0.45 +/- 0.01) after 80 min of perfusion and maternal to fetal clearance was 2.59 +/- 0.24 ml/min. About 16% of TH maternal dose was recovered in the tissue, while 18% appeared in fetal circulation. TH recovery was 89 +/- 9%. On the basis of our results, similar concentrations could be predicted in mother and fetus after maternal TH intake. The TH transfer profile is consistent with in vivo values reported in humans and animals at delivery.

Pharmacokinetics and transplacental passage of imipenem during pregnancy.

Imipenem pharmacokinetics were studied in early pregnancy (n = 7; length of gestation, 8.6 +/- 1.5 weeks, mean +/- standard deviation), in late pregnancy (n = 7; length of gestation, 38.7 +/- 1.4 weeks), and in the nonpregnant state (n = 6). A single dose of 500 mg of imipenem-cilastatin (1:1) was administered as a 20-min infusion. Multiple plasma and urine samples, as well as specimens of umbilical plasma and amniotic fluid from the pregnant subjects, were collected at frequent intervals for 8 h. Imipenem concentrations were assayed by specific microbiologic assay. The mean peak concentrations in plasma were 14.7 +/- 4.9, 14.9 +/- 5.2, and 43 +/- 28.3 micrograms/ml in early pregnancy, late pregnancy, and the nonpregnant state, respectively. The volumes of distribution were significantly larger during early pregnancy (0.98 +/- 0.45 liter/kg of body weight, P < 0.005) and late pregnancy (0.59 +/- 0.19 liter/kg, P < 0.05) than in the nonpregnant state (0.33 +/- 0.10 liter/kg), and total clearances from plasma were faster in early pregnancy (12.7 +/- 7.8 ml min-1 kg-1, P < 0.05) and late pregnancy (10.7 +/- 4.6 ml min-1 kg-1, P < 0.05) than in the nonpregnant state (5.77 +/- 1.19 ml min-1 kg-1). The mean concentrations in amniotic fluid were 0.07 +/- 0.01 and 0.72 +/- 0.85 micrograms/ml in early and late pregnancy. The mean umbilical venous and arterial drug concentrations were 1.72 +/- 1.22 and 1.64 +/- 1.22 micrograms/ml. The feto-maternal ratio at the time of cesarean section was 0.33 +/- 0.12. These results indicate that an adjustment of doses of imipenem may be required when treating pregnant women because of considerable changes in imipenem pharmacokinetics during pregnancy.